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Ultraviolet light induces redox reaction-mediated dimerization and superactivation of oncogenic Ret tyrosine kinases

M Kato1, T Iwashita, K Takeda

  • 1Department of Immunology, Nagoya University School of Medicine, Nagoya, Aichi 466-8550, Japan.

Molecular Biology of the Cell
|January 19, 2000
PubMed

Insights

Ultraviolet light (UV) superactivates Ret kinases, including those linked to multiple endocrine neoplasia (MEN2A and MEN2B). UV-induced free radicals promote disulfide bond-mediated dimerization and activation of Ret proteins, particularly at cysteine 376.

Area of Science:

  • Molecular Biology
  • Oncology
  • Biochemistry

Background:

  • The c-RET proto-oncogene encodes a receptor tyrosine kinase implicated in multiple endocrine neoplasia types 2A (MEN2A) and 2B (MEN2B) due to germline mutations.
  • Mutations associated with MEN2A and MEN2B lead to constitutive activation of Ret kinases (Ret-MEN2A and Ret-MEN2B).

Purpose of the Study:

  • To investigate the effect of ultraviolet (UV) light irradiation on the activation and dimerization of c-Ret, Ret-MEN2A, and Ret-MEN2B kinases.
  • To identify specific amino acid residues and mechanisms involved in UV-induced Ret kinase activation.

Main Methods:

  • Assessing Ret protein dimerization via disulfide bonds before and after UV irradiation.
  • Measuring Ret kinase autophosphorylation activity.
  • Utilizing a Ret-PTC-1 mutant (Ret-PTC-1-C376A) to pinpoint critical cysteine residues.
  • Employing gene transfection to overexpress Cu/Zn superoxide dismutase as a protective agent.

Main Results:

  • UV irradiation induces superactivation of constitutively active Ret-MEN2A and Ret-MEN2B, and activation of c-Ret.
  • UV light promotes disulfide bond-mediated dimerization of Ret proteins, correlating with increased kinase activity.
  • UV irradiation activates and dimerizes the extracellular domain-deleted mutant Ret (Ret-PTC-1).
  • The Ret-PTC-1-C376A mutant shows low basal kinase activity and dimerization, unaffected by UV, suggesting Cysteine 376 is a key UV target.
  • Overexpression of Cu/Zn superoxide dismutase inhibits UV-mediated Ret dimerization and superactivation, indicating a role for free radicals.

Conclusions:

  • UV irradiation activates Ret kinases through promotion of disulfide bond-mediated dimerization.
  • Cysteine 376 in the Ret kinase domain is a critical site for UV-induced activation.
  • UV-induced free radicals likely mediate Ret kinase dimerization and superactivation by targeting intracellular domains.

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